Sheikh A. Saeed

STIMULATION OF PROSTAGLANDIN BIOSYNTHESIS BY DRUGS: EFFECTS in vitro OF SOME DRUGS AFFECTING GUT FUNCTION

1 Low concentrations of several emetic, purgative or irritant drugs in the absence of added co‐factors stimulated conversion of arachidonic acid to prostaglandin E2 and F2α by prostaglandin synthetase extracted from bull seminal vesicles (BSV prostaglandin synthetase). Their effect was dependent on concentration and time. 2 Stimulation of BSV prostaglandin synthetase by apomorphine, aloes, tyramine or zingerone was increased several‐fold by addition of reduced glutathione to the incubation medium, whereas hydroquinone, a phenolic co‐factor of prostaglandin synthetase caused slight depression. 3 From this finding and from the observation that many of the stimulant drugs possess a phenolic group, whereas their inactive relatives lack such a group, it is suggested that these stimulant drugs act as co‐factors for prostaglandin synthetase in place of hydroquinone. 4 Aloes, tyramine, ethanol and quipazine also produced a dose‐related increase in resting tone of the isolated fundus of the rat stomach. This increase occurred at concentrations comparable to those effective in stimulating BSV prostaglandin synthetase, and was abolished by acetylsalicylate. 5 These findings support the view that certain drugs exert some of their pharmacological effects by stimulating prostaglandin synthetase.

Prostaglandins, cyclic AMP and the mechanism of opiate dependence

Abstract Further evidence is given that dependence arises from the agonist action of opiates. From this and our previous propositions assigning a fundamental role to neuronal cyclic AMP in (i) the agonist action of opiates and (ii) the expression of the abstinence syndrome, it follows that opiate dependence is a state of heightened potential activity of a neuronal cyclic AMP mechanism, initiated and maintained by the blockade of an adenylate cyclase. Various possible mechanisms are discussed by which this potential is heightened. New evidence is given that morphine and naloxone stimulate prostaglandin biosynthesis without mutual antagonism. Preliminary evidence also is given that (i) the formation of cyclic AMP is enhanced in brain homogenates from heroin-dependent rats, and (ii) an acidified ethylacetate extract of brains of morphine-dependent rats induces quasi-abstinence effects when injected into a lateral cerebral ventricle of naive rats.

Inhibition of prostaglandin biosynthesis by sulphasalazine and its metabolites.

Sulphasalazine (SZ) inhibits prostaglandin (PG) biosynthesis in vitro with a potency comparable to that of aceylsalicylate. The metabolites of SZ, sulphapyridine and 5-aminosalicylic acid, were of considerably lower potency as inhibitors of PG biosynthesis in the synthetase preparations used. Th inhibition of prostaglandin production by SZ could at least partly account for the clinical utility of sulphasalazine in ulcerative colitis. Sulphapyridine may help to maintain inhibitory concentrations of SZ by restraining bacterial breakdown of the active drug.

Mechanism of quasi-morphine withdrawal behaviour induced by methylxanthines

Of 7 phosphodiesterase inhibitors tested for ability to induce a quasi-morphine withdrawal syndrome (QMWS) in opiate-naive rats, five were effective in a dose-related way. These, in descending order of potency, were IBMX, ICI-63197, RO-201724, theophylline and caffeine. Their potencies in inducing a QMWS correlated significantly (P less than 0.05) with those in inhibiting low Km cyclic AMP phosphodiesterase of rat brain homogenate. There was no correlation with potencies in inhibiting cyclic GMP phosphodiesterase.

On the mode of action and biochemical properties of anti-inflammatory drugs-I

Abstract The horse-radish peroxidase-hydrogen peroxide (HRP-H 2 O 2 ) catalyzed oxidation of o -dianisidine was inhibited by indomethacin, oxyphenbutazone, mefenamic acid, phenylbutazone and p -acetamidophenol. The greatest inhibitory effect ( id 50 0.014 mM) was obtained with indomethacin, and its mode of action in this system has been examined further. The results obtained suggest that indomethacin acted by competing with o -dianisidine for peroxidase and hydrogen peroxide or peroxidase hydrogen peroxide complexes.

Purification of 15-hydroxy prostaglandin dehydrogenase from bovine lung.

Summary 15-Hydroxy prostaglandin dehydrogenase has been isolated in a highly purified state from bovine lung by a simple 3-step procedure. Spectrophotometric studies have shown that this enzyme catalyzes the conversion of PGE 2 (11α,15(S)-dihydroxy-9-ketoprost-5,13-dienoic acid) into 15-keto-PGE 2 ((11α-hydroxy19,15-diketoprost-5,13-dienoic acid).

The local antinociceptive and topical anti-inflammatory effects of propyl gallate in rodents.

1 In common with several anti‐inflammatory, analgesic, local anaesthetic and antioxidant drugs, propyl gallate in vitro inhibited the biosynthesis of prostaglandin E2 and F2α from arachidonic acid by a prostaglandin synthetase from bull seminal vesicles. 2 In common with analgesic drugs, propyl gallate reduced the ability of arachidonic acid, acetylcholine or acetic acid to cause abdominal constrictions in mice. 3 Using a new method of evaluating anti‐inflammatory activity, we demonstrated the effectiveness of aspirin or indomethacin given subcutaneously before u.v. irradiation of guinea‐pig ears, the prophylactic action of topically applied sunscreen agents and the therapeutic value of bufexamac and propyl gallate applied after irradiation.

Prostaglandin synthesis inhibition by maternal and fetal sheep plasma and its relation to haptoglobin and albumin levels

Mammalian plasmas and sera have been reported to contain endogenous inhibitors of prostaglandin synthesis (EIPS), but the identity and role of these suggested inhibitors is as yet undetermined. Albumin and haptoglobin have been proposed as possible inhibitors, and it has been suggested that EPIS may have a part to play in the control of PG production during pregnancy and in the neonatal period. As part of a series of studies aimed at elucidating the identity and role of EIPS, maternal and fetal blood samples were collected from chronically catheterized pregnant ewes, and plasma levels of albumin, haptoglobin and EIPS activity determined. Pregnant ewe plasma possessed high EIPS activity and fetal lamb plasma little or no EIPS activity. Levels of albumin and/or haptoglobin did not consistently parallel that of EIPS activity. A post-operative rise (4 sheep studied) and a pre-parturition nadir (1 sheep studied) in maternal plasma EIPS activity were also noted. The possible physiological significance of these results is discussed.

Comparisons between the abilities of various human and ovine plasmas to inhibit prostaglandin synthesis.

The ability of various human and ovine blood plasmas to inhibit prostaglandin synthesis in vitro has been tested. Human plasmas were significantly more potent in their ability to inhibit prostaglandin synthesis than their counterpart ovine plasmas. In general, female plasma had greater inhibitory activities than male plasmas and adult plasmas were more active than fetal plasmas. There was no simple correlation between the activity of plasmas as inhibitors of prostaglandin synthesis and their respective albumin or haptoglobin contents.

On the mode of action and biochemical properties of anti-inflammatory drugs-II.

The inhibition of prostaglandin (PG) synthetase by nonsteroidal anti-inflammatory drugs (NSAID) is not well understood. Co-factors (glutathione and hydroquinone) are needed for maximum enzymatic activity in vitro, and we suggest that NSAID might inhibit PG synthetase partly by interfering with co-factor induced stimulation of the enzyme. This hypothesis was tested by: A) Examining the effect of glutathione, noradrenaline and hydroquinone on bull seminal vesicle (BSV) PG synthetase in vitro. The stimulatory effects were concentration-dependent. B) Three structurally distinct NSAID, indomethacin, aspirin and paracetamol, inhibited the stimulation by each co-factor in a concentration-related manner. Drug effectiveness also depended on the concentration of co-factor.